Epidermal cells provide the first point of contact for sensory stimuli and are innervated by somatosensory neurons (SSNs) that shape our experience of the world. Both SSNs and epidermal cells are of great clinical relevance; SSNs are mediators of physiological and pathological pain, and some pathological skin conditions are associated with debilitating pain and itch. However, our understanding of roles that epidermal cells play in SSN development and function, particularly nociception, remain limited aside from a few well-studied examples. Characterizing these important intercellular interactions is complicated by the heterogeneity and complexity of vertebrate nervous systems. Drosophila provides an appealing system to close this gap in our knowledge, offering a wealth of genetic resources, ready imaging access of SSNs/epidermis with single cell resolution, a compact nervous system, and evolutionary conservation of key regulators of SSN development/function. In this project we will use an integrated approach to study an evolutionarily conserved intracellular interaction that involves the wrapping of SSN neurites by epidermal cells. The conservation of this intercellular interaction and the preferential ensheathment of nociceptors compared to other SSNs suggest that these sheaths may play key roles in development and function of nociceptive SSNs. Here, we test the hypothesis that epidermal ensheathment of SSNs functionally couples epidermal cells to SSNs. We will test this hypothesis using three lines of experimentation. First, we will characterize the response properties of Drosophila epidermal cells and identify epidermal sensory channels that mediate epidermal responses to noxious stimuli. Second, we will test requirements for sheaths in epidermal activation of nociceptors, define the neuronal substrates for epidermally-gated behavior responses, define the SSN repertoire functionally coupled to epidermal stimulation, and quantify contributions of epidermal activation to sensory-evoked behaviors. Third, we will identify signaling mechanisms linking epidermis and C4da neurons in the periphery and identify circuit- level effects of ensheathment. Given the enormous impact of pathological pain on quality of life ? chronic pain affects more Americans than diabetes, heart disease, and cancer combined ? understanding how epidermal cells modulate nociceptive SSN function is of great interest for development of novel therapeutics for pain management. Successful completion of this project will provide insight into a fundamental component of somatosensation that represents a novel control point for nociception that could define a new entry point for pain management.